Effects of Methapyrilene on Rat Hepatic Xenobiotic Metabolizing Enzymes and Liver Morphology

Effects of Methapyrilene on Rat Hepatic Xenobiotic MetabolizingEnzymes and Liver Morphology. GRAICHEN, M. E., NEPTUN, D. A.,DENT, J. G., POPP, J. A., AND LEONARD, T. B. (1985). Fundam.Appl. Toxicol. 5, 165–174. Short-term treatment of ratswith hepatocarcinogens elicits a consistent pattern of phenotypicchanges in hepatic drug metabolizing enzymes, the most strikingof which is a marked increase in microsomal epoxide hydrolase(EH) activity. The antihistaminic drug methapyrilene inducesa high incidence of hepatocellular carcinoma in F-344 rats.The studies reported here were designed to assess the effectsof methapyrilene on hepatic EH activity, cytochrome P-450-dependentmixed-function oxidase activities, liver morphology, and liver-derivedserum enzymes. Male F-344 rats were treated with three dailyoral doses of methapyrilene-HG, up to 300 mg/kg/day, and weresacrificed 48 hr after the last dose. Hepatic microsomal EHand cytosolic DT-diaphorase activities were increased in a dose-relatedfashion, to 420 and 230% of control, respectively. CytochromeP-450 content and benzphetamine-N-demethylase and ethoxycoumarin-O-deethylaseactivities were concomitantly decreased to 35–50% of control.Serum -glutamyl transpeptidase and alanine aminotransferaseactivities were elevated 22- to 27-fold, and serum bile acidsto 36-fold by treatment with methapyrilene. Periportal lesions,characterized by inflammation, nuclear and nucleolar enlargement,bile duct hyperplasia, and hepatocellular necrosis, were observedfollowing methapyrilene administration. The severity of theperiportal lesion correlated with elevations in the serum chemistryparameters. The increases noted in microsomal EH activity supportsthe suggestion that this enzyme may be a useful biochemicalmarker for exposure to hepatocarcinogens.